The ability of modern analytical techniques to ensure that generic or follow-on versions of biotechnology therapies are comparable
to innovator products is a central issue in establishing a legal process for bringing these products to market. Generic drug
makers, as well as some biotechnology companies, want Congress to authorize the US Food and Drug Administration to approve
similar biologics based on an abbreviated testing-and-application system.
Jill Wechsler
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The Hatch–Waxman Act established such a process for conventional drugs in 1984, but it does not apply to biologics regulated
by the Public Health Service Act. Difficulties in assessing comparability and "sameness" has inhibited FDA from approving
follow-on versions of those biologics regulated under the Food, Drug, and Cosmetic Act (FDCA). Now many manufacturers claim
they have the science and the skill to document the comparability and safety of large molecules and are pressing to overcome
the legal obstacles.
To ensure the safety and efficacy of follow-ons while also protecting markets and preserving research and development incentives,
brand manufacturers insist that all follow-on biologics require additional preclinical and clinical testing. Even then, follow-ons
might not be interchangeable with brands, a situation that would limit patient access and product sales. The debate is heating
up as momentum builds for authorizing follow-on biologics or follow-on proteins (as FDA prefers) as a way to reduce spending
on costly biotechnology therapies. Innovator companies want to keep the issue from blocking the speedy reauthorization of
the prescription-drug user fee program and may be willing to compromise on a measure addressing biotechnology development
and regulation.
The status of the science
In Washington This Month
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All sides agree that science should determine the scope of follow-on testing, but they disagree about where the science stands.
Generics makers maintain that advances in analytical testing can ensure the comparability and safety of follow-on products.
"Our ability to make and characterize protein products and other complex biologics has progressed rapidly in the last few
decades," said Ajaz Hussain, vice-president of Sandoz and former FDA official, in testimony before the Senate Health, Education,
Labor, and Pensions (HELP) Committee in early March 2007.
Small biotechnology and testing companies, moreover, are creating new technical methods to develop follow-ons. One such method
is a protein-characterization platform described by Insmed President Geoffrey Allan at a hearing held by the House Oversight
and Government Reform Committee. Seattle-based Cell Therapeutics recently announced plans to use its genetic polymer technology
to facilitate follow-on development.
These and other manufacturers believe that comparability protocols provide a model for follow-on development and evaluation.
FDA allows innovator firms to use mass spectroscopy and other technologies to demonstrate that significant manufacturing changes—such
as product reformulation or a move to a new plant—yield new products that are essentially the same as the original treatment.
In fact, FDA is encouraging manufacturers to adopt sophisticated quality-by-design production techniques that can limit the
volume of data and testing needed to document comparability following manufacturing changes. The aim is to spur pharmaceutical
companies to make continuous improvements in their manufacturing processes, explained FDA Deputy Commissioner Janet Woodcock
at the House hearing.
But she also noted the need for comprehensive information about the structural aspects of a protein, as well as for a full
understanding of the product's mode of action, to predict clinical comparability. A new manufacturer would not have all the
information about the innovator's intermediate manufacturing steps, Woodcock pointed out, and would bear the burden of demonstrating
that a similar therapy from a different company works the same as the reference product.
